For many years, the development of effective therapeutic agents for fungal diseases (mycoses) has lacked the attention devoted to drugs effective against other infective organisms. The most common mycotic infections are superficial in nature, are not life threatening, and provide little medical impetus to pharmaceutical companies to develop novel treatments. This scenario is changing, however, and while death from fungal disease is not new, the incidence of systemic fungal infections that cause these fatalities is increasing. Ironically, advances in modern medical techniques in other fields (immunosuppressive and/or cytotoxic therapy) and the advent of disease such as Acquired Immuno Deficiency Syndrome (AIDS) are major contributing causes to the increased number of serious fungal infections.
Fungal diseases can, thus, be divided into the life-threatening systemic infections, such as histoplasmosis, systemic candidiasis, aspergillosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, and cryptococcosis, and the more common superficial ones, such as dermatophyte (ringworm) infections, for example, tinea pedis (athlete's foot) and tinea cruris (jock itch), candidiasis, and actinomycosis. The life-threatening fungal infections are a growing problem not only for immunosuppressed or immunocompromised individuals as noted above but individuals with other viral infections, such as cytomegalovirus (CMV), and influenza, for cancer patients receiving chemotherapy or radiotherapy, for transplant patients receiving antirejection agents, and for patients that have received toxic chemicals, metals and radiation exposure.
Mycoses are often caused by fungi which are opportunists, rather than pathogens. Candidiasis, aspergillosis, phycomycosis, nocardiosis, and cryptococcosis are typically opportunistic fungal infections. For example, Candida albicans, is normally found in the alimentary tract as a commensal, yet it is a major cause of systemic fungal infections in immunocomprised patients and topical infections in healthy individuals.
Most drugs currently available for the treatment of mycoses have limited efficacy or are poorly tolerated. A persistent and vexatious problem with antifungal agents, largely unattended by the prior art, is the lack of an agent that is easy and economical to synthesize, and possesses high activity and broad spectrum activity against organisms, low toxicity and limited adverse effects.
Moreover, many known agents merely have fungistatic properties, rather than fungicidal properties. Fungistatic activity is the ability to prevent growth of fungi, while fungicidal (fungitoxic) activity is the ability to kill the fungi. Many agents used in the treatment of superficial mycoses are virtually devoid of either fungistatic or fungicidal actions in the concentrations used, and their beneficial effects probably depend upon factors not related to any direct effect on fungi.
Among the known antifungal agents are the azoles such as imidazoles and triazoles, the polyene macrolide antibiotics, such as nystatin and amphotericin B. as well as the keratolytic agents. The imidazoles and triazoles include ketoconazole, fluconazole, itraconazole miconazole, clotrimazole, and econazole. See, for example, U.S. Pat. No. 4,767,777 issued to Bass et al.; U.S. Pat. No. 4,404,216 issued to Richardson; European Patent Application 0 183 494; F. T. Boyle et al., Annals N. Y. Acad. Science, vol. 544, pp. 86-100 (1988); P. F. Troke et al., Antimicrob. Agents & Chemotherapy, vol. 28, pp. 815-818 (1985) and vol. 27, pp. 832-835 (1985). These drugs have been used in both topical and oral preparations to treat both superficial and systemic infections. The most notable is ketoconazole. However, toxicity (e.g., nausea, anorexia, vomiting) prevents its use in oral form and these together with problems of teratogenicity, enzyme specificity, as well as an idiosyncratic hepatotoxicity syndrome have severely curtailed the usage of this compound.
Amphotericin B and nystatin are most notable among the polyene macrolide antibiotics. Topically, these agents are effective against candidiasis of the skin and mucous membrane, but not against ringworm. Amphotericin B is most effective against systemic fungal infections. However, this drug is not soluble in water and must be prepared in colloidal preparations for intravenous or intrathecal(into the cerebral spinal fluid) use. Sodium or potassium salts must be added to prevent precipitation of the colloid. This drug also cannot be given intramuscularly or orally. Amphotericin B has many adverse effects including severe febrile reaction which almost always occurs. Renal toxicity, hypokalemia, anemia, nausea, weight loss, and phlebitis are also common side effects. For a comparison of efficacies of amphotericin B with fluconazole and itraconazole, see Van't Wout et al., Antimicrob. Agents & Chemotherapy, vol. 33, pp. 147-151 (1989).
The keratolytic agents such as salicylic acid and benzoic acid exert their effect mainly by promoting desquamation of the stratum corneum, especially in hyperkeratotic locations. The fungus resides in the stratum corneum, where keratin is its substrate, not in the toxininduced lesion. Thus, keratosis removes the offending fungus as well as aids in the penetration of drugs.
Other topical agents include undecylenic acid, ciclopirox olamine, haloprogin, and tolnaftate. Undecylenic acid (10-undecenoic acid) is one of several fatty acids and their salts which exhibit primarily fungistatic activity. Ciclopirox olamine and haloprogin have a spectrum of activity similar to the imidazoles. Tolnaftate is very effective against ringworm infections but not effective against Candida species.
In addition to the keratolytic action of benzoic acid, in the agricultural field, certain substituted benzoic acid compounds, that is, certain monosubstituted dinitrobenzoic acid compounds, have been reported to have fungicidal properties. For example, 4-chloro-3,5-dinitrobenzoic acid ester is a known fungicide (see, e.g., Japanese Patent Application 53101528) although reported to be phytotoxic to certain cultivated plants. See U.S. Pat. No, 4,806,151 issued to Bohus et al. U.S. Pat. No. 4,806,151 discloses 4-amino-3,5-dinitrobenzoic compounds having fungicidal as well as herbicidal properties, and suggests that such compounds are not phytotoxic to cultivated plants. While these monosubstituted dinitrobenzoic acid compounds are typically potent fungicides, their toxicity is far too great for animal or human use.
It is noted, however, that the use of 3,5-dichloro-2,6-dinitrobenzoic acid as an antituberculant agent has been disclosed in Russian Patent 1160696 issued to O. F. Ginsburg, V. Z. Gurevich et al.
Thus, despite the plethora of agents which have or are alleged to have antifungal properties, most are simply fungistatic and not fungitoxic. For those that are fungicidal, for example, amphotericin B, there are severe dverse side effects which limit their use and their hemical properties, e.g., solubility, limit drug delivery method. Although opportunistic systemic fungal infections have a high morbidity and mortality and their incidence is increasing, the art has yet to provide a safe, effective water soluble, simple-to-synthesize, fungitoxic agent with a broad antifungal spectrum of activity coupled with limited adverse effects and low toxicity.